Rationale & Objective The approved therapeutic indication for immune checkpoint inhibitors (CPIs) are rapidly expanding including treatment in the adjuvant setting, the immune related toxicities associated with CPI can limit the efficacy of these agents. The literature on the nephrotoxicity of CPI is limited. Here, we present cases of biopsy proven acute tubulointerstitial nephritis (ATIN) and glomerulonephritis (GN) induced by CPIs and discuss potential mechanisms of these adverse effects. Study design, setting, & participants We retrospectively reviewed all cancer patients from 2008 to 2018 who were treated with a CPI and subsequently underwent a kidney biopsy at The University of Texas MD Anderson Cancer Center. Results We identified 16 cases diagnosed with advanced solid or hematologic malignancy; 12 patients were male, and the median age was 64 (range 38 to 77 years). The median time to developing acute kidney injury (AKI) from starting CPIs was 14 weeks (range 6–56 weeks). The average time from AKI diagnosis to obtaining renal biopsy was 16 days (range from 1 to 46 days). Fifteen cases occurred post anti-PD-1based therapy. ATIN was the most common pathologic finding on biopsy (14 of 16) and presented in almost all cases as either the major microscopic finding or as a mild form of interstitial inflammation in association with other glomerular pathologies (pauci-immune glomerulonephritis, membranous glomerulonephritis, C3 glomerulonephritis, immunoglobulin A (IgA) nephropathy, or amyloid A (AA) amyloidosis). CPIs were discontinued in 15 out of 16 cases. Steroids and further immunosuppression were used in most cases as indicated for treatment of ATIN and glomerulonephritis (14 of 16), with the majority achieving complete to partial renal recovery. Conclusions Our data demonstrate that CPI related AKI occurs relatively late after CPI therapy. Our biopsy data demonstrate that ATIN is the most common pathological finding; however it can frequently co-occur with other glomerular pathologies, which may require immune suppressive therapy beyond corticosteroids. In the lack of predictive blood or urine biomarker, we recommend obtaining kidney biopsy for CPI related AKI.

Tertiary lymphoid structures (TLSs) are associated with anti-tumor response following immune checkpoint inhibitor (ICI) therapy, but a commensurate observation of TLS is absent for immune related adverse events (irAEs) i.e. acute interstitial nephritis (AIN). We hypothesized that TLS-associated inflammatory gene signatures are present in AIN and performed NanoString-based gene expression and multiplex 12-chemokine profiling on paired kidney tissue, urine and plasma specimens of 36 participants who developed acute kidney injury (AKI) on ICI therapy: AIN (18), acute tubular necrosis (9), or HTN nephrosclerosis (9). Increased T and B cell scores, a Th1-CD8+ T cell axis accompanied by interferon-g and TNF superfamily signatures were detected in the ICI-AIN group. TLS signatures were significantly increased in AIN cases and supported by histopathological identification. Furthermore, urinary TLS signature scores correlated with ICI-AIN diagnosis but not paired plasma. Urinary CXCL9 correlated best to tissue CXCL9 expression (rho 0.75, p < 0.001) and the ability to discriminate AIN vs. non-AIN (AUC 0.781, p-value 0.003). For the first time, we report the presence of TLS signatures in irAEs, define distinctive immune signatures, identify chemokine markers distinguishing ICI-AIN from common AKI etiologies and demonstrate that urine chemokine markers may be used as a surrogate for ICI-AIN diagnoses.

Background: Immune-related adverse events are a management challenge in patients receiving immune checkpoint inhibitors (ICIs). The most common renal immune-related adverse event, acute interstitial nephritis (AIN), is associated with patient morbidity and mortality. AIN, characterized by infiltration of renal tissue with immune cells, may be analogous to kidney transplant rejection. We evaluated clinical variables and pathologic findings to identify predictors of renal response and overall survival (OS) in patients with ICI-induced AIN. Design, setting, participants, and measurements: We reviewed the records and biopsy specimens of all 35 patients treated for ICI-induced AIN at our institution, between August 2007 and August 2020, who had biopsy specimens available. Two board-certified renal pathologists graded the severity of inflammation and chronicity using transplant rejection Banff criteria and performed immunohistochemistry analysis. Patients were categorized as renal responders if creatinine had any improvement or returned to baseline within 3 months of initiating treatment for AIN. Clinical and pathologic characteristics and OS were compared between responders and non-responders. Results: Patients with high levels of interstitial fibrosis were less likely to be responders than those with less fibrosis (p = 0.02). Inflammation, tubulitis, the number of eosinophils and neutrophils, and the clustering or presence of CD8+, CD4+, CD20+, or CD68+ cells were not associated with renal response. Responders had better OS than non-responders (12-month OS rate 77% compared with 27%, p = 0.025). Responders who received concurrent ICIs had the best OS, and non-responders who did not receive concurrent ICIs had the worst OS (12-month OS rate 100% for renal response and concurrent ICIs, 72% for renal response and no concurrent ICIs, and 27% for no renal response and no concurrent ICIs; p = 0.041). Conclusions: This is the first analysis of ICI induced nephritis where a detailed pathological and clinical evaluation was performed to predict renal response. Low levels of interstitial fibrosis in kidney tissue are associated with renal response to treatment for ICI-induced AIN, and the renal response and use of concurrent ICIs are associated with better OS in these patients. Our findings highlight the importance of the early diagnosis and treatment of ICI-AIN, while continuing concurrent ICI therapy.

Neonatal alloimmune thrombocytopenia (NAIT) presents as isolated thrombocytopenia in a normal neonate as a result of destruction of fetal platelets by maternal antibodies against paternally derived human platelet antigens. Neonatal alloimmune thrombocytopenia affects 0.1% of births, with maternal antibodies crossing the placenta as early as 14 weeks' gestation. Few reports describe placental histopathological changes occurring in NAIT cases. We present a case of NAIT associated with massive chronic intervillositis, a rare entity occurring in 0.06% to 0.8% of reviewed 2nd- and 3rd-trimester placentas; to our knowledge, this is the 1st report of such an association.